Our initial project was to test the hypothesis that the increased cell proliferation and glycogen in the psoriatic lesional epidermis was due to combination of a low cyclic AMP and a high cyclic GMP. Measurements of cyclic AMP levels in the epidermis from normal subjects and the involved and uninvolved epidermis from psoriatic patients revealed that the in vivo levels were approximately the same in all three (the involved psoriatic epidermis showed even slightly higher content than the normal epidermis and normal appearing epidermis of psoriasis). Micro-determinations of cyclic GMP levels demonstrated a marked increase in the involved epidermis. However the question whether this increase is the cause or the result of epidermal cell proliferation has not been answered. In search of hormones and drugs, which stimulate the epidermal cyclic AMP system, we have found four distinct categories: Beta-adrenergic agonists, histamine (also tolazoline), adnosine (and adenine nucleotides) and prostaglandins (E series). In the psoriatic lesional epidermis, we have found a specific deficiency in the catecholamine stimulation. Screening of hormones, which stimulate the cyclic GMP system demonstrated none (only histamine can do so weakly). We have observed no significant difference in the kinetics of specific phosphodiesterases between the involved and uninvolved skin of psoriasis. We are therefore looking for a possible abnormality in the guanylate cyclase system in the involved epidermis of psoriasis.